Coagulation is a host defense system that limits the spread of pathogens. Coagulation proteases, such as thrombin, also activate cells by cleaving PARs. In this study, we analyzed the role of PAR-1 in coxsackievirus B3–induced (CVB3-induced) myocarditis and influenza A infection. CVB3-infected
Silvio Antoniak, A. Phillip Owens III, Martin Baunacke, Julie C. Williams, Rebecca D. Lee, Alice Weithäuser, Patricia A. Sheridan, Ronny Malz, James P. Luyendyk, Denise A. Esserman, JoAnn Trejo, Daniel Kirchhofer, Burns C. Blaxall, Rafal Pawlinski, Melinda A. Beck, Ursula Rauch, Nigel Mackman
Submitter: Jorge Caria1 | firstname.lastname@example.org
Authors: Stuart Connolly2, Michael Ezekowitz3, Martina Brueckmann1, 4, Andreas Clemens1, Salim Yusuf2, and Lars Wallentin5, on behalf of the RE-LY study investigators
Published May 1, 2013
1Boehringer Ingelheim GmbH & Co. KG, Ingelheim, Germany, 2Population Health Research Institute, McMaster University, Ontario, Canada, 3Jefferson Medical College, Wynnewood, PA and Cardiovascular Research Foundation, New York, NY, 4Medical Faculty Mannheim of the University of Heidelberg, Germany, 5Department of Medical Sciences, Cardiology and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden
To the Editor,
We read with interest the article by Antoniak S.1 and colleagues, describing an unexpected protective role for the tissue factor (TF)/thrombin/PAR-1 pathway during infection of mice with coxsackievirus and influenza A virus. Based on preclinical data, the authors extrapolated that the direct thrombin inhibitor dabigatran may increase the risk and severity of viral infection in patients.
We acknowledge the value of preclinical studies in mice as hypothesis generating. However, the hypothesis generated by Antoniak S.1 and colleagues needs confirmation in a clinical setting. As the authors recognize, to date there are no reports of increased rates of viral infection in patients having received dabigatran etexilate. The RE-LY2,3 trial included over 18.000 patients with atrial fibrillation at risk of stroke, in which over 12.000 patients were treated with dabigatran for a mean duration of 2 years. We identified no increased risk of overall infections, including viral infections:
• Infections and infestations rate, reported as any adverse event: 30.5%, 30.6% and 32.9% for dabigatran 110 bid, 150 bid and warfarin, respectively;
• Infections and infestations rate, reported as serious adverse events: 4.0%, 3.9% and 4.1% for dabigatran 110 bid, 150 bid and warfarin, respectively;
• Influenza infections rate (any adverse event): 2.3%, 2.4% and 2.2% for dabigatran 110BID, 150 BID and warfarin, respectively;
• Viral gastroenteritis rate (any adverse event): 0.3%, 0.4% and 0.5% for dabigatran 110BID, 150 BID and warfarin, respectively;
• Unspecified viral infections rate (any adverse event): 0.4%, 0.4% and 0.5% for dabigatran 110BID, 150 BID and warfarin, respectively;
• No cases of myocarditis were reported in RE-LY.
In the placebo-controlled trials RE-DEEM (4) (n=1861) and RE-SONATE (5) (n=1343), with an average exposure to study drug ranging from 159 to 165 days, no imbalance in viral infections rates was identified. If antagonization of thrombin would facilitate (viral) infection, this should in principle also apply to other anticoagulants, including vitamin K antagonists, heparins and other novel oral anticoagulants, but such adverse events have not yet been systematically reported from the clinical setting. To our knowledge, there is also no evidence from the literature about an increased risk of viral infections with other direct thrombin inhibitors, such as bivalirudin, argatroban or ximelagatran. We believe dabigatran provides a significant health benefit when used as directed, addressing an important unmet need in patients with atrial fibrillation at risk of ischemic stroke.6 Concerns raised by Antoniak and colleagues and hypotheses generated in animal models are not supported by clinical evidence.